. The principal theme of this research proposal is the development of modified oligonucleotides that catalyze sequence-specific nucleic acid cleavage under normal cellular conditions. In addition, a study to determine the potential for targeting antisense oligonucleotides against Pneumocystis carinii will be pursued. Specific aims are: (1) Determine mechanism and establish scope of the iron mediated sequence-specific cleavage of nucleic acids by phenanthroline tethered oligonucleotides; (2) Construct second generation metal binding modified oligonucleotides designed for high specificity redox-mediated interstrand cleavage; (3) Develop combinatorial modified oligonucleotide libraries specifically designed to bind metal ions (Mg2+, Zn2+, or Ca2+) to search for new sequence- specific nucleases; (4) Explore strand-invasion strategies for dsDNA targeting and cleavage; (5) Determine the potential of oligonucleotide appended ligands for metal-mediated DNA interstrand cross- linking; and (6) Investigate P. carinii as a potential target for antisense oligonucleotides.